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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2798-2803 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.8344 Multicenter Phase II Study of Fertility-Sparing Treatment With Medroxyprogesterone Acetate for Endometrial Carcinoma and Atypical Hyperplasia in Young Women
From the Japan Gynecologic Cancer Study Group, Tokyo; Department of Obstetrics and Gynecology, Kurume University, Kurume; Department of Obstetrics and Gynecology, Kyushu University; Department of Gynecology, National Kyushu Cancer Center, Fukuoka; Department of Obstetrics and Gynecology, University of Tsukuba, Tsukuba; Department of Obstetrics and Gynecology, Shinshu University, Matsumoto; Department of Obstetrics and Gynecology, University of Tokyo, Tokyo; Department of Gynecology, Aichi Cancer Center Hospital, Nagoya; Department of Obstetrics and Gynecology, Kashiwa Hospital, Jikei University, Kashiwa; Department of Obstetrics and Gynecology, National Kure Medical Center, Kure; Department of Obstetrics and Gynecology, Saga University, Saga; Department of Obstetrics and Gynecology Kagoshima City Hospital, Kagoshima; Department of Gynecology, Niigata Cancer Center, Niigata; Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo; Department of Obstetrics and Gynecology, Tottori University, Yonago; Department of Obstetrics and Gynecology, Tohoku University, Sendai; Department of Gynecology, National Shikoku Cancer Center, Matsuyama; Department of Pathology, Kyorin University, Mitaka; Department of Pathology, National Defense Medical College, Tokorozawa; and the Department of Pathology, Third Hospital, Jikei Medical University, Komae, Japan Address reprint requests to Kimio Ushijima, MD, PhD, Department of Obstetrics and Gynecology, Kurume University School of Medicine, 67 Asahi-Machi, Kurume 830-0011, Japan; e-mail: kimi{at}med.kurume-u.ac.jp
Purpose: To assess the efficacy of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women. Patients and Methods: This multicenter prospective study was carried out at 16 institutions in Japan. Twenty-eight patients having EC at presumed stage IA and 17 patients with AH at younger than 40 years of age were enrolled. All patients were given a daily oral dose of 600 mg of MPA with low-dose aspirin. This treatment continued for 26 weeks, as long as the patients responded. Histologic change of endometrial tissue was assessed at 8 and 16 weeks of treatment. Either estrogen-progestin therapy or fertility treatment was provided for the responders after MPA therapy. The primary end point was a pathologic complete response (CR) rate. Toxicity, pregnancy rate, and progression-free interval were secondary end points. Results: CR was found in 55% of EC cases and 82% of AH cases. The overall CR rate was 67%. Neither therapeutic death nor irreversible toxicities were observed; however, two patients had grade 3 body weight gain, and one patient had grade 3 liver dysfunction. During the 3-year follow-up period, 12 pregnancies and seven normal deliveries were achieved after MPA therapy. Fourteen recurrences were found in 30 patients (47%) between 7 and 36 months. Conclusion: The efficacy of fertility-sparing treatment with a high-dose of MPA for EC and AH was proven by this prospective trial. Even in responders, however, close follow-up is required because of the substantial rate of recurrence.
Endometrial carcinoma (EC) in women younger than 40 years of age represents 2% to 14% of all cases. Obesity, ovarian dysfunction such as polycystic ovary (PCO) syndrome, and nulliparity are risk factors. Histologically, 90% of cases are well differentiated (grade 1 [G1]) endometrioid adenocarcinoma, frequently accompanied by endometrial hyperplasia.1-4 The incidence of myometrial invasion and lymph node metastasis are rare.5,6 Atypical endometrial hyperplasia (AH) is a precancerous lesion, and approximately 30% of the cases will progress to EC within several years.7 The standard treatment for EC is staging laparotomy, including hysterectomy and bilateral salpingo-oophorectomy. The 5-year survival rate exceeds 93% in stage IA disease.8 Thus, young patients with EC at stage IA are cured by the standard treatment in exchange for losing their fertility. The conservative treatment for young women with EC and AH who desire to conceive has been a challenging issue. Some case reports have revealed that synthesized progestins such as medroxyprogesterone acetate (MPA) are effective as a conservative treatment of AH and G1 EC.9-13 In our retrospective study, 15 of 18 women with AH and 9 of 12 women with G1 EC at presumed IA stage showed CR with MPA treatment.9 Nevertheless, there have been no prospective trials to investigate the optimal dosage, duration of treatment, curative rate of MPA treatment, or pregnancy rate after this therapy in young women with EC and AH. Therefore, we conducted a multicenter, prospective phase II study on MPA treatment.
Sixteen institutions belonging to the Japan Gynecologic Cancer Study Group were registered. Eligible patients were between 20 and 39 years, had histologically confirmed AH or G1 EC at presumed stage IA, and desired to preserve fertility. Endometrial tissue sampling for diagnosis should be carried out by dilation and curettage (D&C). Other inclusion criteria were Eastern Cooperative Group performance status of 0 to 1, no prior treatment for endometrial lesion, body mass index (BMI) of less than 35, adequate hepatic and renal function, no abnormality in blood coagulation tests nor history of thromboembolism. All patients received pelvic magnetic resonance imaging before registration, and myometrial invasion or any extra uterine lesion was ruled out by institutional radiologist. The protocol was reviewed and approved by the institutional review board of each participating center, and all patients gave written informed consent before participation.
Treatment
Evaluation of Response and Follow-Up
Patient Characteristics Although 47 patients were enrolled onto this study, two patients were excluded due to G2 EC by CPR diagnosis. The 45 eligible patients receiving MPA treatment consisted of 28 with EC and 17 with AH. All patients were nulligravida. The age of the patients ranged from 22 to 39 (mean 31.7 ± 2.8). BMI ranged from 16.0 to 32.7 (mean 22.8 ± 3.9). Twenty-seven of the 45 (60%) patients had a history of irregular menstrual period, and 7 of the 45 (16%) satisfied criteria for PCO syndrome (Table 1).
Histopathologic Diagnosis by CPR Among the 47 patients, discrepancies in the histologic diagnosis between CPR and each institution before treatment were found in nine patients (Table 2). Seven patients were between the diagnosis of G1 EC and AH. Two cases were excluded from the study because CPR changed the diagnosis of G1 to G2. Thus, the rate of agreement between institutional and CPR diagnoses was 81%.
Response to MPA Treatment Clinical response was summarized in Table 3. Among the 28 patients with EC, six voluntarily withdrew from this study and underwent hysterectomy before completion of the protocol treatment, even though they showed PR at 8 weeks. Among the 22 patients who completed the protocol treatment, 12 patients showed CR. Thus, the CR rate per protocol was 55% (12 of 22 patients). Three patients with EC who showed NC at 16 weeks underwent hysterectomy. Regarding the 17 AH patients, no one withdrew from the protocol. Fourteen of the 17 patients showed CR at 26 weeks. The CR rate for AH was 82% (14 of 17 patients). Accordingly, a total of 26 patients showed CR, and the CR rate per protocol was 67% (26 of 39 patients). Among the 26 patients with CR, six of 12 EC patients (50%), and nine of 14 AH patients (64%) showed CR at 8 weeks. Eleven of 12 EC patients (92%) and 12 of 14 AH patients (86%) showed CR at 16 weeks (Table 4). No patients with PD were recorded during the MPA treatment. There were no correlations between treatment response and clinical characteristics such as PCO and BMI.
Endometrial Thickness Measurement of endometrial thickness using TVUS was available in 41 patients. Data were analyzed according to the final response to MPA treatment. Among the 27 EC patients, the endometrium during the treatment of 12 CR patients was significantly thinner than that of 15 PR or NC patients (ie, the endometrial thickness was 6.5 ± 3.5 mm at 8 weeks and 4.2 ± 1.4 mm at 16 weeks in CR patients). In PR and NC patients, it was 14.7 ± 9.3 mm at 8 weeks and 10.3 ± 6.8 mm at 16 weeks. Among the 14 AH patients, however, there was no remarkable difference in endometrial thickness between CR and non-CR patients. Among the 27 EC patients, 11 patients with an 8-week endometrial thickness thinner than pretreatment had a CR rate of 73% at 26 weeks. In contrast, 16 patients with an 8-week endometrial thickness thicker than pretreatment had a CR rate of only 25%.
Adverse Effect
Pregnancy Outcome
PFI and Recurrence During the follow-up period (25 to 73 months; median, 47.9 months), a recurrent lesion in the endometrium was found in 14 (47%) of the 30 patients, including eight (57%) of 14 EC and six (38%) of 16 AH. Median PFI was 34.6 months in EC and 44.2 months in AH. There was no statistical difference in either the recurrence rate or PFI between EC and AH. However, recurrence was seen in eight (73%) of 11 patients having anovulatory cycles during the observation period, whereas in only six (32%) of 19 patients having ovulatory cycles. In addition, recurrence was found in 11 (69%) of 16 patients who had an observation period without use of estrogen-progestin therapy or fertility treatment (2 to 52 months). Thus, patients who had anovulatory cycles or treatment-free periods had significantly higher rates of recurrence. After the diagnosis of recurrence, eight of 14 patients who still desired fertility were treated by MPA treatment again. Six of them showed an initial disappearance of lesion, but lesion recurred in five patients. Throughout the observation period, one patient developed an extrauterine lesion. She had achieved CR at 26 weeks of the protocol treatment, and then received MPA therapy three more times for repeated recurrences. Exploratory laparotomy at 2 years after the initial MPA treatment revealed peritoneal carcinomatosis. Pathologic study of the samples from the peritoneum and surface of the resected ovary revealed G2 endometrioid adenocarcinoma without papillary serous carcinoma element. The patient died of disease 4 months after surgery. The disease was speculated as synchronous malignancies of both endometrial and peritoneal carcinomas because there was no endometrial malignancy 3 months before the development of the peritoneal lesions.
Pathology of Surgical Specimens
As the number of younger women with EC has increased, fertility-sparing treatment has received much attention. Since the early 1980s, there have been several reports on conservative treatment with progestins for early-stage endometrial cancer in young women. Most of them were small series and retrospective studies from single institutions. Response rates and recurrence rates varied9-13 (ie, the response rate for EC and AH ranged from 57% to 76% and 83% to 92%, respectively, and the recurrence rate ranged from 11% to 50%). Such variations were probably due to the differences in drugs used, dosage, and duration of treatment. Daily doses of megestrol acetate ranged between 10 and 400 mg, and that of MPA ranged between 200 and 800 mg. In our previous multicenter retrospective study, 600 mg of MPA revealed a higher response rate than those of 400 and 200 mg.9 Therefore, our prospective study was conducted to clarify the accurate CR rate of treatment with MPA at a fixed dose of 600 mg/d for 26 weeks, and has demonstrated that the CR rate for EC and AH was 55% and 82% respectively, and the recurrence rate was 57% and 38%, respectively. Among the patients who achieved CR, approximately half of them were diagnosed as CR at 8 weeks, and 92% of them were CR at 16 weeks of treatment. There were eight patients who were considered as CR for the first time at 16 weeks. Some histologic change corresponding to PR was recognized from all of their 8-week D&C specimens. These results must be distinguished from nonresponders. Meanwhile, nonresponders at 8 weeks can hardly have a chance to achieve CR. The most serious toxicity of MPA was thought to be thromboembolism. In this study, however, no patients suffered from thromboembolism, including six obese patients with a BMI of more than 30. Cotreatment of 600 mg of MPA with 81 mg of aspirin was considered safe up to 26 weeks. Another important problem in conservative therapy was the lack of confidence in the pathologic diagnosis on endometrial tissue. A Gynecologic Oncology Group study revealed concurrent EC was found in 42.6% of the hysterectomy specimens of the patients diagnosed as AH by endometrial biopsy in the community hospital.14 Kaku et al9 reported 10 pathologic discrepancies among 39 patients with G1 EC and AH. Thus, substantial numbers of AH cases might be included in the previous studies of conservative treatment for EC. However, in this study, all the specimens for initial diagnosis were obtained by D&C. CPR was conducted by the same pathologists as in the previous retrospective study.9 These factors brought accurate diagnoses and contributed to the difference in the CR rate between EC and AH. Among three AH patients who received hysterectomy, EC was found in the hysterectomy specimens of the two patients. Nevertheless, one patient was refractory to MPA and hysterectomy was carried out at 7 months after the initial diagnosis, and the other patient underwent hysterectomy at recurrence after 9 months of remission. Most researchers will agree that the indication for fertility-sparing treatment is restricted to presumed IA stage. Nevertheless, the diagnostic accuracy of myometrial invasion by imaging studies is limited. In detecting myometrial invasion by magnetic resonance imaging, the rate of accuracy varied between 68% and 82%.15 CT scan failed to identify myometrial invasion in 39% of patients.16 This study also showed that seven of 19 patients who underwent hysterectomy had minimal myometrial invasion. Therefore, we should recognize that a small number of patients with EC having myometrial invasion will be included in the fertility-sparing treatment protocol. We had four more patients who achieved CR after an additional 3 to 6 months of MPA treatment following 26 weeks of treatment. It might be acceptable if only for the PR patients to continue MPA treatment for an additional 6 months. Nevertheless, longer-term hormonal treatment cannot be warranted for poor responders. The present study has shown the usefulness of TVUS for assessment of the response to MPA treatment. TVUS studies demonstrated that good responders of EC had an endometrium statistically thinner than that of poor responders at both 8 and 16 weeks. In addition, thinner endometrium at 8 weeks than at pretreatment predicted CR at 26 weeks with 73% possibility, whereas CR will be obtained in only 25% of cases with thicker endometrium at 8 weeks than at pretreatment. Therefore, observation of endometrial thickness by TVUS during MPA treatment had a predictive value for responders. On the other hand, there were no correlations between the response to MPA and the endometrial thickness at pretreatment, or other clinicopathologic characteristics such as PCO or BMI, indicating the difficulty in the selection of ideal patients suitable for this treatment. Conception is the ultimate goal of fertility-sparing treatment. Nevertheless, young patients with EC tended to have fertility problems. Case reports showed that most EC patients who successfully conceived after conservative treatment underwent infertility therapy, including assisted reproductive technologies.17,18 Jadoul and Donnez reported19 that 55% of 17 pregnancies after progestin treatment were brought on by IVF. In this series, 11 of 12 pregnancies were brought about using infertility therapy, including five cases by IVF-ET, suggesting that immediate infertility treatment is recommended for patients in this setting. Even in responders, EC subsequently developed recurrence with a considerably high incidence.9,11,12 Patients who desire to conceive should have ovulatory induction, and those who do not wish to conceive should be treated by cyclic estrogen-progestin therapy. Recent reports have revealed that levonorgestrel IUD well suppressed a hyperplastic endometrium.20 Although, the efficacy of progestin IUD for EC remains unclear, it may be an alternative to estrogen-progestin therapy during the observation period for patients who do not desire to conceive at that moment. On the other hand, longer-term or repeated hormonal treatment should be avoided, as patients with EC younger than 40 years were reported to have a two to seven times higher risk for ovarian carcinoma or peritoneal carcinomatosis than those at older ages.21,22 In fact, we encountered two patients with ovarian lesion considered as synchronous malignancy, and another patient who developed peritoneal carcinomatosis 2 years after initial MPA treatment. Our multicenter prospective study showed fertility-sparing treatment with MPA to be an effective therapy with the least toxicities for young patients with AH and those with G1 EC at presumed IA stage. Nevertheless, EC lesions may recur at a considerably high frequency, and patients may develop synchronous malignancy in the ovary or peritoneum, which clearly indicates that a patient's excessive anticipation of fertility preservation may threaten her life. Patients should be informed of the risks and limitations of this conservative treatment. The validity of prophylactic hysterectomy and bilateral adnexectomy for those patients who have elected to stop bearing children is still uncertain. Further investigation is needed for the application of this procedure.
The authors indicated no potential conflicts of interest.
Conception and design: Hiroyuki Yoshikawa Administrative support: Kimio Ushijima Provision of study materials or patients: Kimio Ushijima, Hideaki Yahata, Hiroyuki Yoshikawa, Ikuo Konishi, Toshiharu Yasugi, Toshiaki Saito, Toru Nakanishi, Hiroshi Sasaki, Fumitaka Saji, Tsuyoshi Iwasaka, Masayuki Hatae, Shoji Kodama, Tsuyoshi Saito, Naoki Terakawa, Nobuo Yaegashi, Masamichi Hiura Collection and assembly of data: Kimio Ushijima, Hideaki Yahata, Toshiharu Yasugi, Toshiaki Saito, Toru Nakanishi, Hiroshi Sasaki, Fumitaka Saji, Tsuyoshi Iwasaka, Masayuki Hatae, Shoji Kodama, Tsuyoshi Saito, Naoki Terakawa, Nobuo Yaegashi, Masamichi Hiura Data analysis and interpretation: Kimio Ushijima, Hideaki Yahata, Hiroyuki Yoshikawa, Ikuo Konishi, Atsuhiko Sakamoto, Hitoshi Tsuda, Masaharu Fukunaga, Toshiharu Kamura Manuscript writing: Kimio Ushijima, Toshiharu Kamura Final approval of manuscript: Hideaki Yahata, Hiroyuki Yoshikawa, Ikuo Konishi, Toshiharu Kamura
We thank Kazuo Kuzuya, MD, Makoto Yasuda, MD, Toshio Hirakawa, MD, and Tsuneo Fujii, MD, for assisting with this study.
Supported by a Grant-in-Aid for research of cancer treatment from the Ministry of Health, Labor, and Welfare of Japan (No.14-10). Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Author's disclosures of potential conflicts of interests are found at the end of this article.
1. Crissman JD, Azoury RS, Barnes AE, et al: Endometrial cancer in women 40 years of age or younger. Obstet Gynecol 57:699-704, 1981 2. Gallup DG, Stock RJ: Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 64:41-421, 1986 3. Gitch G, Hanzal E, Hacker NF, et al: Endometrial cancer in premenopausal women 45 years and younger. Obstet Gynecol 85:504-508, 1995[Abstract] 4. Kaku T, Matsuo K, Tsukamoto N, et al: Endometrial carcinoma in women aged 40 years or younger: A Japanese experience. Int J Gynecol Cancer 3:147-153, 1993[CrossRef][Medline] 5. Creasman WT, Morrow CP, Homesley HD, et al: Surgical pathologic spread patterns of endometrial cancer. Cancer 60:2035-2041, 1987[CrossRef][Medline] 6. Boronow RC, Morrow CP, Creasman WT, et al: Surgical staging in endometrial cancer: Clinical-pathologic findings of a prospective study. Obstet Gynecol 63:825-832, 1984 7. Kurman RJ, Kaminski PE, Norris HJ: The behavior of endometrium hyperplasia: A long term study of untreated hyperplasia in 170 patients. Cancer 56:403-412, 1985[CrossRef][Medline] 8. Creasman WT, Odicino F, Pecorelli S, et al: Carcinoma of the corpus uteri: FIGO annual report on the result of treatment in gynaecological cancer. J Epidemiol Biostatics 6:45-86, 2001 9. Kaku T, Yoshikawa H, Kamura T, et al: Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: Central pathologic review and treatment outcome. Cancer Lett 167:39-48, 2001[CrossRef][Medline] 10. Gotlieb W, Beiner ME, Ben-Baruch G, et al: Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 102:718-725, 2003 11. Kim YB, Holschneider CH, Montz FJ, et al: Progestin alone as primary hormonal treatment of endometrial carcinoma in premenopausal women, report of seven cases and review of the literature. Cancer 79:320-327, 1997[CrossRef][Medline] 12. Randall TC, Kurman RJ: Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 90:434-440, 1997[Abstract] 13. Imai M, Jobo T, Sato R, et al: Medroxyprogesterone acetate therapy for patients with adenocarcinoma of the endometrium who wish to preserve the uterus-usefulness and limitations. Eur J Gynaecol Oncol 22:217-220, 2001[Medline] 14. Trimble CL, Kauderer J, Zaino R, et al: Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia A gynecologic Oncology Group Study. Cancer 106:812-819, 2006[CrossRef][Medline] 15. Ben-Shachar I, Vitellas KM, Chon DE: The role of MRI in the conservative management of endometrial cancer. Gynecol Oncol 93:233-237, 2004[CrossRef][Medline] 16. Zerbe MJ, Bristow R, Grumbine FC, et al: Inability of preoperative computed tomography scans to accuracy predict the extent of myometrial invasion and extracorporal spread in endometrial cancer. Gynecol Oncol 78:67-70, 2000[CrossRef][Medline] 17. Paulson R, Sauer MV, Lobo RA: Pregnancy after in vitro fertilization in a patient with stage I endometrial carcinoma treated with progestins. Fertile Sterile 54:735-736, 1990 18. Kimming R, Strowitzki T, Muller-Hocker J, et al: Conservative treatment of endometrial cancer permitting subsequent triplet pregnancy. Gynecol Oncol 58:255-257, 1995[CrossRef][Medline] 19. Jadoul P, Donnez J: Conservative treatment may be beneficial for young women with atypical endometrial hyperplasia or endometrial adenocarcinoma. Fertile Sterile 80:1315-1324, 2003[CrossRef] 20. Ørbo A, Rise CE, Mutter G: Regression of latent endometrial precancers by progestin infiltrated intrauterine device. Cancer Res 66:5613-5617, 2006 21. Walse C, Hoscheider C, Hoang Y, et al: Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol 106:693-699, 2005 22. Evans-Metcalf ER, Brooks SW, Baker SP, et al: Profile of women 45 years of age and younger with endometrial cancer. Obstet Gynecol 91:349-354, 1998[Abstract] Submitted August 22, 2006; accepted March 1, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test and two sample t-test were employed for statistical analysis. Significance was held at the standard value of P < .05. The primary end point was the pathologic CR rate. Adverse effect, overall survival, progression-free interval (PFI), pregnancy rate, and recurrence rate were secondary end points. Hormone receptors were not examined in this study. 
) Continuous Estrogen Progestin therapy is recommended in observation
